Endocrinologic, Genetic, and Metabolic Disease

Gene mutation analysis and long-term follow-up of 6-pyruvoyltetrahydropterin synthase deficiency in Qingdao

  • Yaoyao ZHONG ,
  • Liqin ZHANG ,
  • Wei DU ,
  • Weibing LU ,
  • Tingting LIU
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  • Women and Children's Hospital, Qingdao University, Qingdao 266034, Shandong, China

Received date: 2022-11-07

  Online published: 2023-02-16

Abstract

Objective To investigate the screening, clinical manifestations, genetic variants and long-term follow-up results of 6-pyruvoyltetrahydropterin synthase deficiency (PTPSD) in Qingdao. Methods Two hundred and fifty-one children with hyperphenylalaninemia (HPA) in Qingdao Women and Children's Hospital from November 1998 to December 2021 were included, and urinary pterin profile test, erythrocyte dihydropteroate reductase activity test, tetrahydrobiopterin (BH4) loading test, and genetic test were performed to confirm the diagnosis of PTPSD. The incidence, gene mutations and long-term follow-up of PTPSD were analyzed. Results Twenty-six children were diagnosed as tetrahydrobioptenin deficiency (BH4D), all PTPSD, and the incidence of PTPSD among newborns in Qingdao was 12.7 per million. 19 children (from 17 families) underwent genetic testing, and 10 variants were detected among 34 alleles of PTS, with the higher frequency of variants being c.259C>T (29.4%, 10/34), and the rest were c.286G>A (14.7%, 5/34), c.272A>G (14.7%, 5/34), c.84-291A>G (8.8%, 3/34), c.166G>A (8.8%, 3/34), c.276T>A (8.8%, 3/34 ), and the variant sites were mainly concentrated in exon 5 (67.6%, 23/34). Among them, c.200C>T, c.259C>T and c.286G>A may be associated with severe PTPSD. Conclusion The incidence of PTPSD in Qingdao is 12.7/ million in 1996-2021, and the hotspot variants of PTS gene are c.259C>T, c.286G>A, c.272A>G. Establishment of a complete integrated management system of newborn disease screening-diagnosis-treatment-long-term follow-up-assistance is a powerful measure to achieve a tertiary prevention of birth defects and reduce the occurrence of disabled children.

Cite this article

Yaoyao ZHONG , Liqin ZHANG , Wei DU , Weibing LU , Tingting LIU . Gene mutation analysis and long-term follow-up of 6-pyruvoyltetrahydropterin synthase deficiency in Qingdao[J]. Journal of Clinical Pediatrics, 2023 , 41(2) : 103 -107 . DOI: 10.12372/jcp.2023.22e1473

References

[1] van Spronsen FJ, Blau N, Harding C, et al. Phenylketonuria[J]. Nat Rev Dis Primers, 2021, 7(1): 36.
[2] Opladen T, López-Laso E, Cortès-Saladelafont E, et al. Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies[J]. Orphanet J Rare Dis, 2020, 15(1): 126.
[3] Elhawary NA, AlJahdali IA, Abumansour IS, et al. Genetic etiology and clinical challenges of phenylketonuria[J]. Hum Genomics, 2022, 16(1): 22.
[4] 中华医学会儿科学分会内分泌遗传代谢学组,中华预防医学会中华预防医学会出生缺陷预防与控制专业. 高苯丙氨酸血症的诊治共识[J]. 中华儿科杂志, 2014, 52(6): 420-425.
[5] 张立琴, 何怡峰, 宋扬, 等. 四氢生物蝶呤缺乏症7例早期临床诊断及治疗[J]. 中国儿童保健杂志, 2005, 13(2): 127-128.
[6] Moammar H, Cheriyan G, Mathew R, et al. Incidence and patterns of inborn errors of metabolism in the Eastern Province of Saudi Arabia, 1983-2008 [J]. Ann Saudi Med, 2010, 30(4): 271-277.
[7] Khatami S, Dehnabeh SR, Zeinali S, et al. Four years of diagnostic challenges with tetrahydrobiopterin deficiencies in Iranian patients[J]. JIMD Rep, 2017, 32: 7-14.
[8] 陈挺, 赵正言, 蒋萍萍, 等. 高苯丙氨酸血症表型与基因型研究进展[J]. 浙江大学学报(医学版), 2018, 47(3): 219-226.
[9] 吕书博, 赵德华, 张琳琳, 等. 河南地区6-丙酮酰四氢蝶呤合成酶缺乏症基因变异分析[J]. 中华实用儿科临床杂志, 2020, 35(9): 691-694.
[10] Yuan X, Zhu J, Liu H, et al. Birth prevalence of tetrahydrobiopterin deficiency in China: data from the national newborn screening program, 2013-2019 [J]. J Pediatr Endocrinol Metab, 2021, 34(7): 835-841.
[11] Ye J, Yang Y, Yu W, et al. Demographics, diagnosis and treatment of 256 patients with tetrahydrobiopterin deficiency in mainland China: results of a retrospective, multicentre study[J]. J Inherit Metab Dis, 2013, 36(5): 893-901.
[12] Li N, Yu P, Rao B, et al. Molecular genetics of tetrahydrobiopterin deficiency in Chinese patients[J]. J Pediatr Endocrinol Metab, 2018, 31(8): 911-916.
[13] Th?ny B, Blau N. Mutations in the BH4-metabolizing genes GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase, sepiapterin reductase, carbinolamine-4a- dehydratase, and dihydropteridine reductase[J]. Hum Mutat, 2006, 27(9): 870-878.
[14] Oppliger T, Th?ny B, Kluge C, et al. Identification of mutations causing 6-pyruvoyl-tetrahydropterin synthase deficiency in four Italian families[J]. Hum Mutat, 1997, 10(1): 25-35.
[15] Imamura T, Okano Y, Shintaku H, et al. Molecular characterization of 6-pyruvoyl-tetrahydropterin synthase deficiency in Japanese patients[J]. J Hum Genet, 1999, 44(3): 163-168.
[16] Liu TT, Chiang SH, Wu SJ, et al. Tetrahydrobiopterin-deficient hyperphenylalaninemia in the Chinese[J]. Clin Chim Acta, 2001, 313(1-2): 157-169.
[17] Manti F, Nardecchia F, Banderali G, et al. Long-term clinical outcome of 6-pyruvoyl-tetrahydropterin synthase-deficient patients[J]. Mol Genet Metab, 2020, 131(1-2): 155-162.
[18] Chiu YH, Chang YC, Chang YH, et al. Mutation spectrum of and founder effects affecting the PTS gene in East Asian populations[J]. J Hum Genet, 2012, 57(2): 145-152.
[19] Li L, Yang H, Zhao J, et al. Identification and molecular analysis of 11 cases of the PTS gene variants associated with tetrahydrobiopterin deficiency[J]. Front Genet, 2022, 13: 919209.
[20] Himmelreich N, Blau N, Th?ny B. Molecular and metabolic bases of tetrahydrobiopterin (BH4) deficiencies[J]. Mol Genet Metab, 2021, 133(2): 123-136.
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